The development and maturation of blood vessels results from a complex interplay of pro- and anti-angiogenic regulators. Dysregulation of the balance between these factors is thought to result in the formation of pathological blood vessels, such as blood vessels with increased vascular permeability (Bergers & Benjamin, Nat. Rev. Cancer 3:401-410 (2003)). Increased vascular permeability has been implicated in numerous pathologies; non-limiting examples include vascular diseases and disorders of the eye, diabetes, cancer, pulmonary hypertension, and various edemas.
As one non-limiting example, consider the eye. The eye contains highly vascularized and completely avascular tissues in close apposition. This specialized anatomy requires regulation of the balance between vascular quiescence and vascular growth (Schlingemann et al., Br. J. Ophthalmol. 81:501-51 (1991)). In eye diseases associated with angiogenesis and vascular permeability, this delicate balance is disturbed. Some leading causes of severe vision loss and blindness are ocular-related disorders wherein the vasculature of the eye is damaged or insufficiently regulated. Ocular-related diseases with a vascular permeability element include, for example, exudative age-related macular degeneration, diabetic retinopathy, corneal neovascularization, choroidal neovascularization, neovascular glaucoma, cyclitis, Hippel-Lindau disease, reinopathy of prematurity, pterygium, histoplasmosis, iris neovasularization, macular edema, glaucoma-associated neovascularization, and the like. Vision loss may be caused by increased vessel permeability, or increased vessel permeability may be correlated with one or more symptoms which impair the eye's function or otherwise inconvenience or cause discomfort in the patient. As non-limiting examples, accumulation of fluid within the eye and the vitreal cavity can instigate retinal detachment, degeneration of sensory cells of the eye, increased intraocular pressure, and inflammation, all of which adversely affect vision and the general health of the eye.
As another non-limiting example, there are two kinds of diabetic retinopathy. The first is non-proliferative retinopathy, which is an earlier stage of the disease characterized by increased capillary permeability, microaneurysms, hemorrhages, exudates, and edema. Most vision loss during this stage is due to the fluid accumulating in the macula due to vascular leakage. This accumulation of fluid is called macular edema and can cause temporary or permanent decreased vision. Prolonged periods of vascular leakage can ultimately lead to the thickening of the basement membrane and formation of soft and hard exudates. The second category of diabetic retinopathy is called proliferative retinopathy and is characterized by abnormal new vessel formation, which grows on the vitreous surface or extends into the vitreous cavity. These newly formed blood vessels of the retina or choroid are often permeable, which allows leakage of vascular fluid into the surrounding tissue and formation of fibrotic tissue and scarring. The leakage of material from the vasculature into the tissues of the eye and scarring can lead to vision loss.
For many ocular-related disorders, including retinal, choroidal, and macular edema, there are no efficient therapeutic options currently available. Laser photocoagulation is employed to administer laser burns. For example, focal macular photocoagulation is used to treat areas of vascular leakage outside the macula (Murphy, Amer. Family Physician 51(4):785-796 (1995)). Advanced proliferative retinopathy is commonly treated with scatter or panretinal photocoagulation. The laser treatment may cause permanent blind spots corresponding to the treated areas. Laser treatment may also cause persistent or recurrent hemorrhage, induce neovascularization or fibrosis, or increase risk of retinal detachment. In addition, some patients fail to respond to laser treatments.
Treatments for ocular diseases or conditions and other types of permeability-related diseases or conditions which have decreased dangerous side-effects would be advantageous.
Another disease or disorder characterized by increased vascular permeability is pulmonary hypertension. Pulmonary hypertension is a rare blood vessel disorder of the lung in which the pressure in the pulmonary artery (the blood vessel leading from the heart to the lungs) rises above normal levels and may become life threatening. One cause of pulmonary hypertension is alveolar hypoxia, which results from localized inadequate ventilation of well-perfused alveoli or from a generalized decrease in alveolar ventilation. Pulmonary hypertension is also a vascular permeability related disease. Pulmonary hypertension has been historically chronic and incurable with a poor survival rate. Treatment of pulmonary hypertension usually involves continuous use of oxygen. Pulmonary vasodilators (e.g., hydralazine, calcium blockers, nitrous oxide, prostacyclin) have not proven effective, and lung transplant is often required for patients who do not respond to therapy.
While illustrative ocular disorders and pulmonary hypertension were described above, they are merely non-limiting examples of a few of the types of problems which can be caused by increased vascular permeability. In addition to ocular diseases and disorders and pulmonary hypertension, increased vascular permeability has been found to play a role in the pathophysiology of a variety of other diseases and disorders.
Despite the prevalence of vascular permeability-related disorders, there remains a need for better therapeutic treatments thereof.